Nu-allyl-1, 2-diphenylethylamine



Patented Apr. 18, 1950 sNroFFic-a f Nmmndanrrmrmmmm I v Louis ILGoodson, cityiMo and'ltober-t v, 1 ,Br' Moflett, Mich, assignorsto George A. Breon & Company,

/ a corporation of Missouri Kansas"City, Mo.,

No Drawing; Original application A gust '22, 1946, Serial No. 692,378. Divided and this al plication November 2, l948 Seriai No.- 58,(l14; it y 1 1 This invention relates to' therapeutic compo-1, sitions and more particularly to analgesics.

Among the several objects of the invention may be noted the provision of new analgesic compositions; the provision" of new I analgesic compositions that are readily solublein avail:v able solvents to form stable solutions; the provision of new analgesic compositions that are readily administered; the provision of analgesic compositions that are relatively non-toxic and i Claim. (01. zoo-510.9)

cause noserious complications or side reactions following administration; the provision of methods for manufacturing analgesic compositions of the class indicated that are characterized by their high yield, inexpensive and readily procurable reaction materials, and the facility with which they may be carried out; and the provision of new secondary amines having analgesic properties. Other objects will be in part apparent and in part pointed out hereinafter.

The invention accordingly comprises the ingredients and combinations of ingredients, the

2 i The analgesic compositions of the present invention were tested for their therapeutic efflcacy by the -following method, Adult male albino white "mice were injected subcutaneously under the skin of the back just anterior to the tail. After a certain time interval, e. g. 10 minutes, a mouse so treated was placed on a hot circular plate surrounded 'by a hollow transparent cylinder. The time required for the mouse to show the effect of the heat, called hereinafter the reaction time, was determined by noting how long the mouses hind feet would remain im-.

mobile or be normally active. The mouse would then be removed from the heated plate and after another time interval, e. g. 10 minutes, would be retested for reaction time. This procedure was repeated until the reaction time was less than a control time. This control time for proportions thereof, steps and sequence of steps,

and features of composition and synthesis, analysis, or metathesis, which will be exemplified in the products and processes hereinafter described,- and the scope of the application of which wil be indicated in the following claim.

According to the present invention analgesic compositions having desirable properties are provided. They areeasily soluble in desired proportions in water, and are capable of being stored for long periods of time without being chemically, therapeutically or physically affected. The

each mouse was measured by determining how long the mouse, before injection, would remain on the heated plate without the abnormal movement of the hind feet referred to above.

The reaction time for the analgesic compositions described subsequently was found to be substantially greater than the control time, and no harmful after effects of any type were noted;

A suflicient number of normal mice were used in all tests to be sure that susceptibility due to age variations and other physical conditions were minimized. The fatal doses of the various compositions of the class described were also determined and found to be at concentrations substantially greater than the desired concenamount administered for effective analgesic action is substantially lower than that which is toxic. -It has been found that analgesic compositions of the class described can be readily made in the form of powders, tablets, capsules, and ampules, to be' used for any desired type of administration.

The analgesic compositions of the present invention have as an essential ingredient thereof, one or more compounds of the following formula: I Y

, RIIIQ V Bil QR! H:CH--NHR-HC1 where R is an alkyl alkenyl or fl-hydroxyethyl radical and R R" and R' are the same or different and are hydrogen, hydroxy, alkoxy or .alhlenedioxv radicals.

trations for efiective analgesic action.

The amine ingredients of the analgesic c0mp0-' pared by the direct alkylation of the appropriate 1,2-diarylethylamine with agents such as dimethyl sulfate, ethylene chlorohydrin, and alkyl chloride or similar alkylating agents and then separating the desired secondary amine from the reaction product.

Another method of preparation is the treata Bchifl's base or the formula 3 ment of a 1,2-diaryiethylhalide with the appropriate amine such as methyl amine, etc. and separating the secondary amine produced.

The reduction by catalytic or other means, of

Aryl-OHr-O-Aryl' gives a secondary amine of this type also.

A secondary amine of this type also may be prepared by the hydrogenation of a ketoneor the type Aryl-CHa-CO-Aryl' in the presence of a catalyst and a primary amine.

While there are other methods of preparing the amines used in making the analgesic compositions of the present invention, the methods already outlined are preferred. The following examples .illustrate the present invention. They areexemplary only.

EXAMPLE 1 N-methyl-l- (3-methoxy-4-hydroryphenyl) 2-phenylethvlamine hydrochloride H 1 TOOK:

H:- H-NHCHr-HOI 3-methoxy -4- hydroxybenzalmethylamlne was prepared by heating a suspension'of 76.07 g. of vanillin and 18.6 g. of methylamine in 300 ml.

of benzene and removing the water formed in the reaction by refluxing the benzene with a continuous water separating device. The product was crystallized first from benzene and then from dioxane giving white crystals. M. P. l31-l34.5 C.

A solution of 33.8 g. of this product in 100 ml. 01' hot dry dioxane was added to a stirred solution of benzyl magnesium chloride (prepared irom 19.5 g. of magnesium, 92 ml. of benzyl chlo ride, and 300 ml. of dry ether). After refluxing for some time, the mixture set to a solid and the lumps were then broken up and added to ice and hydrochloric acid. On standing a crystalline precipitate separated which was recrystallized from methanol giving white crystals of the hydrochloride which melts at 178-l80 C. and on continued heating of the sample it resolidified and melted again at 227-230 C. This product was dissolved in triple-distilled water to make an analgesic composition of the desired concentration, suitable for administration.

EXAMPLE2 lV-methul-I -(3-hydr0:r11phenul) -2-phenylethulamine hydrochloride TOE Hr- H-NHCHg-HOI methanol.

200 ml. or dry ether), The mixture became very thick and ml. of dry benzene were added to facilitate stirring. After decomposing the reaction mixture with ice and hydrochloric acid, the layers were separated and the aqueous layer was concentrated in vacuo. The hydrochloride crystallized out and was recrystallized from The -M. P. was 201-202 C. This product was dissolved in triple-distilled water to make an analgesic composition of the desired concentration, suitable for administration.

EXAMPLE3 N- (p-hzldroryethyl) -1-(4-methoa:yphenyl) -2- phenulethylamine hydrochloride OCH:

Hr-tn-Nn-cmomorr-nc 1 A mixture of 68 g. of anisic aldehyde, 34 g. of ethanolamine and 200 ml. of benzene was vigorously shaken for one hour and thewater liberated in the reaction was removed by drying over anhydrous potassium carbonate. The organic solution was distilled and the fraction boiling at 106-109 C. at about 0.03 mm., freezing point 35 C., was collected.

To a solution of benzyl magnesium chloride prepared from 19.5 g. of magnesium, 92 ml. of benzyl chloride and 300 ml. of dry ether was added a solution of 32.6 g. of the .above intermediate in 100 ml. of dry ether. After refluxing for one hour the mixture was treated with ice water and hydrochloric acid. The aqueous layer was separated and washed with ether and made strongly basic with sodium hydroxide. The aqueous suspension of magnesium hydroxide was extracted repeatedly with ether and the ether solution was washed with water and dried over potassium carbonate. The ether solution was distilled and the colorless amine, B. P. C. at 13 mm., was collected, n 1.5727; 11 1.0982.

The amine was converted into its hydrochloride by passing a stream of hydrogen chloride gas through a solution of it in dry ether. The hydrochloride was recrystallized from absolute alcohol. The M. P. was 154-1555 C. This product was dissolved in triple-distilled water to make 'an analgesic composition of the desired concentration for administration.

v EXAMPLE 4 N-aZlyl-I,Z-diphenylethylamine hydrochloride -To a solution of benzyl magnesium chloride prepared from 19.5 ggof magnesium, 92 ml. of benzyl chloride and 300 ml. of dry ether, was added a solution of 29.1 g. of benzylallylamine in 50 ml. of dry ether. After refluxing for one hour the mixture was decomposed with ice and hydrochloric acid. The hydrochloride of the amine separated as a white crystalline precipitate and was collected on a filter, washed with water and ether and dried. After recrystallization from methanol it melted at 206-207.5 C. This 16 product was dissolved in triple-distilled water to N-methill 1 2,: ai tnon myz) -2-phen1 l- 7 cthvlamine hydrochloride (kHz-ISH-NKOHa-HOIQ amine to a solution ofHClfin H Y The amine hydrochloride{was precipitated; washed with dryv ether. The M. P. was 139-1419.

dietmed s ile-12 0'. c'. at;0.06-0.13s m-mn iscis. v

The hydrochloride was I 'C. This product wasdiuolved intriple-distilled 2,3 dimethoethylamine pre *j' pared from 83.13.01 2,3'-dimethoxyben zs1dehyd eand'18.6 8.0! metbylamine of benzene by refluxing thebenzene'withfa water separating device; 'After removing in vacuo the product was distilled. The B. P. was 132 C.at-12mm.

a similar method to that described .inExample 4,'35.-8 g. of product were allowed to react with benzyl unichloride. The hydrochloride was crystallized from the decomposed reaction mixture and recrystallizedfrom methanol. The M. P. was 104-125" C. This product was dissolved in triple-distilled water to make an analgesic composition of the desired 2-hydroxy-3-methoxybenzal methylamine was prepared from 83.1 g. of 2-hydroxy-1-methoxy- 4 benzaldehyde and 18.69 g. of methylamine by the method described in Example 5. It distilled at 132 C. at 12 mm.

A solution of g. of this in 50 ml. of dry ether was allowed to react with benzyl magnesium chloride (prepared from 12.7 g. of magnesium, 60 ml. of benzyl chloride, and 200 ml. of dry ether). The reaction mixture was decomposed with ice and hydrochloric acid and an oily layer of the hydrochloride remained insoluble in both the water and ether layers. This was separated and dried in a vacuum desiccator and then crystallized from a mixture of absolute methanol and absolute ether. The M. P. was 176-179" C. This product was dissolved in triple-distilled water to make an analgesic composition of the desired concentration.

EXAMPLE 7 N -methyl-1- (4-methozyphenyl) -2-phe1wlethylamine hydrochloride H, H-NH-CHa-HC] p-methoxyphenyl ben'zyl ketone 19 g. and methyl formamide 19.8 g. were heated at 180- 210 C. for six hours in a distillation apparatus. The mixture was then refluxed six hours with a mixture of ml. of concentrated HCl and 100 ml. of water. After cooling, the water solution water to make an composi 1 5 desired concentration. i f i amateur-Manama)atheism; f.

amine em-en-;Nacn,rrcr A mixtureof 36.7 g. ofpabout 16 g. of methylamine, zene was shaken vigorously rm- 1 and then the solvent was refluxed, using a continuous water separating device. During the refluxing. the p-hydroxybenzalmethylamine and, after cooling, it was collected, dried, and recrystallized from dioxane; M. P. 175-177JC.

To a solution of benzyl. n :n prepared from 19.5 g. of um, 92 ml. of benzyl chloride and 300 ml. of dry ether, was slowly added a solution of 27 g. of the above phydroxybenzal methylamine in 250 ml. of warm dry dioxane. Themixture became very thick and 200 m1. of dry benzene were added to facilitate stirring. After refluxing for two hours withstirring, themixture was decomposed with ice and hydrochloric acid. The layers were separated and after washing the aqueous layer with ether it was made basic by adding an excess of solid sodium carbonate. The mixture was extracted twice with n-butanol and then with ether and the combined extracts were dried over sodium sulfate. The solvent was distilled in vacuo and the residue was taken up in methanol, treated with decolorizing charcoal, and concentrated. Some 4-hydroxystilbene separated (M. P. 186- 187 C.) which was discarded. The filtrate was saturated with hydrogen chloride gas and then diluted with ether to turbidity. After standing, the solution was filtered from a small amount of crystalline precipitate ofunknown composition and poured into water. The aqueous solution was washed with ether and distilled in vacuo to a small volume which crystallized in cooling. The

crystals were dissolved in methanol, diluted with ether, and cooled in the refrigerator. Crystals of the amine hydrochloride separated and were collected and dried. The M. P. was ITO-173 c. On continued heating at the melting point of the sample, it crystallized and remelted at "sac-224 C. This product was dissolved in triple-distilled water to make an analgesic composition of the desired concentration.

was decanted and made strongly basic with sodium hydroxide. The crude product which sepa- ExAM'PLE9 N -metI wl-1 (3,4-methylenediomhenyl) -2 phenylethylamine hydrochloride and mo mLof- H chloride amiss v 7 A solution of 32.8 a. ct piperonal methylamine in 50 ml. of ether was allowed to react with benzyl magnesium chloride by a method similar to that described in Example 4. Aiter recrystallization from methanol, the hydrochloride melted at 239- 242 C. This product was dissolved in triple-distilled water to make an analgesic composition of the desired concentration.

nxaurm 1o N-methyl-i- (3,4-dimethomhenvl) -2- phenylethvlamine hydrochloride OCH;

distilled water to make an analgesic composition of the desired concentration.

EXAMPLEII N-methyl-l (Z-hydroxyphenyl) -2-phenulethvlamine hydrochloride By a method similar to that described in Example 4 this amine hydrochloride was made from benzyl magnesium chloride and 27 g. of salicylal methylamine. After recrystallization from a mixture of absolute ethanol and absolute ether, the amine hydrochloride melted at 185-l89 C. This product was dissolved in triple-distilled water to make an analgesic composition of the desired concentration.

EXAMPLE 12 N-methyl-I -(3-etho:ryphenyl) Z-phenylethulamine hydrochloride By a method similar to that described in Example 5, m-ethoxybenzal methylamine was prepared i'rom 30 g. of m-ethoxybenzaldehyde and 10 g. of methylamine. The B. P. was 122 C. at 12 mm.

By a method similar to that described in Example 4, 22.7 g. of this product were allowed to react with benzyl magnesium chloride (prepared from 14.6 g. of magnesium, 69 ml. of benzyl chloride, and 200 ml. of dry ether) The amine hydrochloride was recrystallized from methanol. The M. P. was I'll-175 C. This product was dissolved in triple-distilled water to make an analgesic composition or the desired concentration.

iv-methyz-z-(z-methommyn -2- phenylethylamine hydrochloride OOH:

onr on-mi-om-noi By a method similar to that described in Example 4, 25.4 g. of o-methoxybenzal methylamine were allowed to react with benzyl magnesium chloride (prepared from 16.6 g. 01 um, '79 ml. of benzyl chloride. and 275 ml. of dry ether). The amine hydrochloride separated from the decomposed reaction mixture as an oil which was separated and dried in a vacuum desiccator. It was crystallized from anhydrous acetone, M. P. 123-l25 C. This product was dissolved in tripledistilled water to make an analgesic composition oi. the desired concentration.

EXAMPLE 14 N-methyl-l -r(4-methoa:uphenul) -2- (i-methoxyphenyl) ethylamine hydrochloride C H30 0 C H:

A mixture of 132 g. of desoxyanisoin, 118 g. of methyl formamide and 1 ml. of acetic acid was heated at 180-205 C. for twenty-eight hours. The mixture was cooled, washed with water, and the organic layer was boiledfor six hours with a mixture of 200 ml. of concentrated hydrochloric acid and 500 ml. of water. After cooling, the

7 aqueous layer was made strongly alkaline with sodium hydroxide. The resulting crude product (15 g.) melted at 56-58 C. and without purification was converted into its hydrochloride and crystallized from acetone with a yield of 7.1 g. The M. P. was 156-459 C. This product was dissolvedin triple-distilled water to make an 1analgesic composition of the desired concentraion.

In any of theamines described, one or more oi the hydrogens on the phenyl groups can be replaced by an alkyl radical.

EXAMPLE 15 N-fl-hydroxyethyl-I,Z-di-pmethozwphenyb. ethylamine hydrochloride 00H, OCH;

Desoxyanisoin (30 g.), ethanolamine (8 g.), acetic acid (0.2 g.), and benzene (200 ml.) were refluxed using a continuous water separator until no more water was liberated (about six hours). The benzene was then removed under reduced pressure and replaced with absolute alcohol ml.). Sodium metal (12 g.) was added rapidly to the boiling alcohol solution through a. reflux condenser. when the sodium had dissolved the alcohol was removed and the residue was washed with water. The resulting crude N-p-hydroxy- Analgesic compositions of other types than the solutions described above may be prepared. Tablets, capsules, ampules or powders, for example, may be made in the usual way employing the customary diluents, extenders, solvents, contain ers and the like, together with the amines described above. Such analgesic compositions may include more than one of the amines if desired, and the concentration of the amine or amines may be varied to vary the analgesic efiect.

In view of the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained.

As many changes could be made in the above processes and products without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense.

10 This application is a division of our copending U. 8. Patent application S. N. 692,378, filed August 22, 1946.

We claim: N -allyl-1,2-diphenylethylamine.

LOUIS H. GOODSON. ROBERT B. MOFFE'IT.

REFERENCES CITED The following references are of record in the. file of this patent:

UNITED STATES PATENTS Number Name Date 1,989,325 Lommel Jan. 29, 1935 2,006,114 Rosenmund et al. June 25, 1935 2,276,587 Mettler et a1 Nov. 17, 1942 9 OTHER REFERENCES Stevens et al., J. Chem. Soc. (London) 1931, 2568-2572.

Ingersoll et al., J. Am. Chem. Soc., vol. 58, p. 1808-1811 (1936).

Tainter et al., Chem. Abst. vol. 37, p. 3501 (1943).

McPhee et al., J. Am. Chem. Soc., vol. 68, p. 1866-1867 (1946). 

